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TRRAP is essential for regulating the accumulation of mutant and wild-type p53 in lymphoma
- Source :
- Blood. 131:2789-2802
- Publication Year :
- 2018
- Publisher :
- American Society of Hematology, 2018.
-
Abstract
- Tumors accumulate high levels of mutant p53 (mutp53), which contributes to mutp53 gain-of-function properties. The mechanisms that underlie such excessive accumulation are not fully understood. To discover regulators of mutp53 protein accumulation, we performed a large-scale RNA interference screen in a Burkitt lymphoma cell line model. We identified transformation/transcription domain-associated protein (TRRAP), a constituent of several histone acetyltransferase complexes, as a critical positive regulator of both mutp53 and wild-type p53 levels. TRRAP silencing attenuated p53 accumulation in lymphoma and colon cancer models, whereas TRRAP overexpression increased mutp53 levels, suggesting a role for TRRAP across cancer entities and p53 mutations. Through clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 screening, we identified a 109-amino-acid region in the N-terminal HEAT repeat region of TRRAP that was crucial for mutp53 stabilization and cell proliferation. Mass spectrometric analysis of the mutp53 interactome indicated that TRRAP silencing caused degradation of mutp53 via the MDM2-proteasome axis. This suggests that TRRAP is vital for maintaining mutp53 levels by shielding it against the natural p53 degradation machinery. To identify drugs that alleviated p53 accumulation similarly to TRRAP silencing, we performed a small-molecule drug screen and found that inhibition of histone deacetylases (HDACs), specifically HDAC1/2/3, decreased p53 levels to a comparable extent. In summary, here we identify TRRAP as a key regulator of p53 levels and link acetylation-modifying complexes to p53 protein stability. Our findings may provide clues for therapeutic targeting of mutp53 in lymphoma and other cancers.
- Subjects :
- 0301 basic medicine
Lymphoma
Immunology
Biology
Biochemistry
03 medical and health sciences
Protein Domains
Transcription (biology)
RNA interference
Cell Line, Tumor
Humans
Gene silencing
Gene Silencing
Adaptor Proteins, Signal Transducing
Regulation of gene expression
Protein Stability
Ubiquitination
Wild type
Nuclear Proteins
Acetylation
Proto-Oncogene Proteins c-mdm2
Cell Biology
Hematology
Histone acetyltransferase
HDAC1
3. Good health
Cell biology
Gene Expression Regulation, Neoplastic
Protein Transport
030104 developmental biology
Histone
Mutation
Proteolysis
biology.protein
Tumor Suppressor Protein p53
Subjects
Details
- ISSN :
- 15280020 and 00064971
- Volume :
- 131
- Database :
- OpenAIRE
- Journal :
- Blood
- Accession number :
- edsair.doi.dedup.....3447100b70ac548225b163d993bf5caa